The Human Genome & Disease

Question 1

Describe mutations

Answer 1

• Mutations can be inherited or aquired
• Mutations are permanent changes to DNA sequence

Question 2

What are the two different types of mutations (the two cells that mutations happen in)?

Answer 2

• Germline mutations: mutations that are inherited and passed on via the gametes
• Somatic mutations: mutations that are acquired by the somatic cells if DNA get damaged or is copied incorrectly. Not passes on to the next generation

Question 3

What do mutations do/whatare their effects?

Answer 3

• Genetic variations/mutations are a driving force for evolution
• Mutations can have a beneficial effect, no effect, to a deleterious (damaging/harmful) effect on the organism
• Most mutations have no effect
• The outcome of a mutation can also depend on:
  
  • Environmental effects (eg. diet, exposure to toxins)
  • Other genes (‘genetic background’)

Question 4

Why do we classify mutations?

Answer 4

• Mutations can be classed in a lot of ways because they are complex and biological (hence messy)
• The molecular basis of a mutation is not consistent
• Mutations in a single gene can have different effects. That’s why we talk about alleles
• Here we are going to concentrate on two ways of thinking about mutations
  
  • Dominant vs recessive
  • Loss of function vs gain of function

Question 5

Describe dominant vs recessive genes

Answer 5

• Humans are diploid
• This means we have two copies of each of their genes (one maternal and one paternal)
• A mutation (allele) can thus be either heterozygous (one mutant, one wild type allele)
• Or homozygous (both alleles mutant)
• A dominant mutation is one that causes a phenotype when heterozygous
• A recessive mutation is one that causes a phenotype only when homozygous

Question 6

Describe loss of function vs gain of function

Answer 6

• For a mutation (allele) to have a phenotype, it must affect the function of a gene
• A mutation might break a gene to cause it not to work as well as normal, or not work at all
  
  • This is called a ‘loss of function’ mutation (these are often recessive, because a normal copy of the gene exists on the other chromosome which can replace the lost function)
• Sometimes a mutation can cause a gene to work too well, or to do something unexpected
  - This is called a ‘gain of function’ mutation (these are often dominant, because having an allele that works too well or does something novel, will not be replaced by the normal copy of the gene).

Question 7

What can examining the inheritance pattern of an allele tell us?

Answer 7

If it is dominant or recessive - and that can help us understand if it is loss or gain of function. Also if it is X-linked, Y-linked or autosomal

Question 8

What are the examples and characteristics of autosomal recessive mutations?

Answer 8

Examples:
- Inability to taste PTC
- Cysistic fibrosis

Charactaristics:
- Typically not seen in every generation of an effected family.
- Passed on by two asymptomatic carriers
- Males and females equally likely to inherit

Question 9

What are examples and characteristics of autosomal dominant mutations?

Answer 9

Examples:
- Widow’s peak
- Huntingtons disease

Characteristics:
- Occurs commonly in a pedigree
- Affected individuals have an affected parent
- Males and females equally likely to inherit

Question 10

What are examples and characteristics of X-linked recessive mutations?

Answer 10

Examples:
- Haemophilia A
- Haemophilia B

Characteristics:
- Fathers cannot pass X-linked traits onto their sons
- No male-to-male transmissions
- Most often affects males

Question 11

How do we determine the inheritance pattern?

Answer 11

• Examine the pedigree and look for individuals that break the rules above
• Identify carriers who do not have the condition, if there are none, this might mean the condition is dominant
• Find the inheritance pattern that explains all the disease occurrence in a pedigree.
  Think! (pedigrees are often misleading)

Question 12

What is the process of finding potential disease genes?

Answer 12

• sequence genome(s)
• map to human reference
  
  • Common variants
  • novel variants
• Novel variants
  
  • predicted to be harmful
  • predicted to be benign
• Predicted to be harmful: validate and test

Question 13

Describe polygenic disorders

Answer 13

• most disorders appear to have a genetic basis but do not follow straightforward inheritance patterns
• polygenic disorders involve several genes acting together or environmental factors interacting with genes. examples include: obesity, diabetes, rheumatoid arthritis, gout, bipolar disorder
• identifying genes associated with polygenic disorders is very hard

Question 14

How do we find polygenic disease genes?

Answer 14

Cases: 10-100K
Controls: 10-100K
- identify variations
- common variants
- shared variation in cases not in controls
- validate and test (are variants in genes likely to be associated with the disease?)

Question 15

Describe genetic determinism (for diseases)

Answer 15

• For most diseases, having a disease-related variation does not mean you will get the disease
• Such diseases come about through a combination of variants and the environment
• different sufferers may have different disease mechanisms
• most genetic disorders are PROBABILISTIC, not deterministic
• this is also true of most traits with a genetic component, your genes do not direct you destiny